Since receipt of this award, the proposed studies have evolved to incorporate the use of neonatal model systems to characterize the developmental aspects of immune system product exposure as well as the ability of viral antigens to induce certain neurochemical and neuroendocrine events normally associated with the stress response. The proposed developmental studies have been designed to investigate the impact that viral exposure and immune system peptides have upon neonatal development. Particularly relevant to the study of mental health is evidence that exposure to viral antigens during the neonatal period can permanently alter behavioral as well as reproductive-hormonal measures in the adult. The extent to which the CNS mediated consequences may be due to the immune response to an antigen is the subject of these studies. A variety of cytokines - several of which are now known to alter neuroendocrine patterns in adults - will be administered to neonates during the "critical period" when these patterns are first becoming established. Also to be tested will be viral antigen that we have recently shown to alter brain levels of norepinephrine. Following this exposure during the neonatal period, the animals will be closely monitored for: 1) the impact upon subsequent onset of a variety of reflexive behaviors, 2) altered release patterns of reproductive and pituitary-adrenal hormones and 3) the consequences of these neonatal treatments upon immune system measures. In addition, in vitro model systems will be utilized to localize the site(s) of action of the anticipated effects, some of which have already been demonstrated in our pilot studies. The proposed stress experiments have been designed to evaluate the effects of acute and chronic restraint and electric footshock upon certain molecular and functional parameters of immunity, both basal and in response to an immunologic challenge. These effects will then be correlated with both cerebral and peripheral responses to the stressful treatments. In addition, we will study whether treatment with thymosin peptides can alter stress-induced changes in immunity. Stress-associated parameters to be measured will include brain concentration of catecholamines, indoleamines, and their catabolites, and plasma corticosterone. Immunologic measures will include a variety of both quantitative and qualitative measures of immune system activity. These data will be integrated with our current knowledge of the interactions between the pituitary-adrenal system, the catecholaminergic system and host- defense.